The nicotinic receptor at the olivocochlear synapse: from molecules to physiology

ELGOYHEN AB

Cambridge, UK

Conferencia; Conference Meeting, Nicotinic Acetylcholine Receptors; 2008

Acetylcholine (ACh) is the principal neurotransmitter released by medial olivocochlear efferent axons, and existing data suggest a central role for an atypical nicotinic cholinergic receptor (nAChR) located at the synapse between efferent fibers and vertebrate outer hair cells. Current data support a model in which ACh-gated depolarization is followed by activation of small-conductance, calcium-activated potassium channel (SK2) and subsequent hair cell hyperpolarization. We have been able to define the molecular structure of the mammalian hair cell nAChR, and have demonstrated that it is assembled from both a9 and a10 nAChR subunits, in a 2:3 stoichiometry. Although homomeric channels assembled from the a9 nAChR subunit are functional in vitro, electrophysiological, anatomical, and molecular data suggest that native cholinergic olivocochlear function is mediated via heteromeric nAChRs composed of both a9 and a10 subunits. To gain insight into a10 subunit function in vivo, we have recently examined olivocochlear innervation and function in a10 null mutant mice. Electrophysiological recordings from P8-9 outer hair revealed that a proportion of a10-/- but not a9-/- outer hair cells showed small ACh-evoked currents. However, in a10-/- mutant mice, olivocochlear fiber stimulation failed to suppress distortion products, suggesting that the residual a9 homomeric nAChRs expressed by outer hair cells are unable to transduce efferent signals in vivo. An evolutionarily diverged a10 subunit capable of assembling with a9 and conveying new properties to the nAChR is therefore apparently required to obtain classical olivocochlear efferent effects. Our results complement our previous phylogenetic and evolutionary analysis of the a10 subunit indicating that a10 has likely evolved to give the auditory system a feedback control capability over the co-evolved somatic electromotility that is not required in non-mammalian species.